Background and aim There are efficacy and safety concerns related to teneligliptin treatment. A systematic review of randomized controlled trials (RCTs) was undertaken to comprehensively profile the efficacy and safety of teneligliptin in the treatment of type 2 diabetes mellitus (T2DM). Methods Thirteen studies were chosen from a search of scientific databases for RCTs using teneligliptin as a monotherapy or as an adjunct to other glycemic agents with pre-specified inclusion criteria. We calculated weighted mean differences (WMDs) and 95% confidence intervals (CIs) in each included trial and pooled the data using a random-effects model. Results Thirteen studies enrolled 2853 patients were identified. Teneligliptin treatment was associated with weight gain (vs. placebo, weighted mean difference (WMD) 0.28 kg; 95% CI − 0.20–0.77 kg; I 2  = 86%; P  = 0.25). Compared to monotherapy, add on therapy with teneligliptin showed significant improvement in FPG mg/dl levels (WMD − 16.75 mg/dl; 95% CI − 19.38 to − 14.13 mg/dl), HOMA- β (WMD 7.91; 95% CI 5.38–10.45) and HOMA-IR (WMD − 0.27; 95% CI − 0.46 to − 0.07). The improvement in HbA1c was greater with monotherapy (WMD − 8.88 mmol/mol; 95% CI − 9.59 to − 8.08 mmol/mol). There was no significant risk of any hypoglycemia with teneligliptin compared to placebo (OR 0.84; 95% CI 0.44–1.60; I 2  = 0%; P  = 0.60). However, the risk was 1.84 times high when combined with other glycemic agents. The risk of cardiovascular events was comparable, regardless of treatment duration when compared to placebo or any other active comparator (OR 0.79; 95% CI 0.40–1.57; I 2  = 0%; P  = 0.50). PROSPERO, CRD42022360785. Conclusions Teneligliptin is an effective and safe therapeutic option for patients with T2DM, both as monotherapy and as add-on therapy. However, additional large-scale, high-quality, long-term follow-up clinical trials with diverse ethnic populations are required to confirm its long-term efficacy and safety.